PUBLICATIES

Hieronder een aantal wetenschappelijke online publicaties waarbij PHORECAST in verband met onderzoek een directe rol heeft gespeeld. Deze publicaties zijn meestal in de Engelse taal geschreven en gepubliceerd. Klik op de links voor de volledige weergave van de online artikelen.

 

In augustus 2014 is opnieuw een publicatie over de p.Arg14del mutatie in het PLN gen verschenen, ditmaal in Circulation Cardiovascular Genetics. In dit artikel is onderzocht hoe de sterfte van PLN R14del dragers zich verhoudt tot de algemene bevolking en welke risicofactoren er zijn voor het ontwikkelen van ernstige hartritmestoornissen.

Outcome in phospholamban R14del carriers: results of a large multicentre cohort study

+ Abstract


+ Background
The pathogenic phospholamban R14del mutation causes dilated and arrhythmogenic right ventricular cardiomyopathies and is associated with an increased risk of malignant ventricular arrhythmias and end-stage heart failure. We performed a multicentre study to evaluate mortality, cardiac disease outcome, and risk factors for malignant ventricular arrhythmias in a cohort of phospholamban R14del mutation carriers.

+ Methods and Results
Using the family tree mortality ratio method in a cohort of 403 phospholamban R14del mutation carriers, we found a standardized mortality ratio of 1.7 (95% confidence interval, 1.4-2.0) with significant excess mortality starting from the age of 25 years. Cardiological data were available for 295 carriers. In a median follow-up period of 42 months, 55 (19%) individuals had a first episode of malignant ventricular arrhythmias and 33 (11%) had an end-stage heart failure event. The youngest age at which a malignant ventricular arrhythmia occurred was 20 years, whereas for an end-stage heart failure event this was 31 years. Independent risk factors for malignant ventricular arrhythmias were left ventricular ejection fraction below 45% and sustained or nonsustained ventricular tachycardia with hazard ratios of 4.0 (95% confidence interval, 1.9-8.1) and 2.6 (95% confidence interval, 1.5-4.5), respectively.

+ Conclusion
Phospholamban R14del mutation carriers are at high risk for malignant ventricular arrhythmias and end-stage heart failure, with left ventricular ejection fraction below 45% and sustained or nonsustained ventricular tachycardia as independent risk factors. High mortality and a poor prognosis are present from late adolescence. Genetic and cardiac screening is, therefore, advised from adolescence onwards.


van Rijsingen IA, van der Zwaag PA et al. Circ Cardiovasc Genet. 2014;7:455-65. doi: 10.1161/CIRCGENETICS.113.000374

Op 12 april 2013 is opnieuw een publicatie over de p.Arg14del mutatie in het PLN gen verschenen, in het Netherlands Heart Journal. In dit artikel wordt onder meer de geografische spreiding van dragers van de p.Arg14del mutatie in Nederland beschreven. Hieronder kunt u het abstract lezen en de afbeeldingen met de spreiding van de mutatiedragers en de oorsprong van deze mutatie zien.

Recurrent and founder mutations in the Netherlands: phospholamban p.Arg14del mutation causes arrhythmogenic cardiomyopathy

+ Abstract


+ Background
Recently, we showed that the c.40_42delAGA (p.Arg14del) mutation in the phospholamban (PLN) gene can be identified in 10-15% of Dutch patients with dilated cardiomyopathy or arrhythmogenic cardiomyopathy. The arrhythmogenic burden of the p.Arg14del mutation was illustrated by the high rate of appropriate ICD discharges and a positive family history for sudden cardiac death.

+ Methods
Our goal was to evaluate the geographical distribution and the origin of this mutation and to estimate the prevalence in a Dutch population cohort. We investigated the postal codes of the places of residence of p.Arg14del mutation carriers and places of birth of their ancestors. In addition, a large population-based cohort (PREVEND) was screened for this mutation.

+ Results
By April 2012, we had identified 101 probands carrying the PLN p.Arg14del mutation. A total of 358 family members were also identified, resulting in a total of 459 mutation carriers. The majority of mutation carriers live in the northern part of the Netherlands and analysing their grandparents’ places of birth indicated that the mutation likely originated in the eastern part of the province of Friesland. In the PREVEND cohort we identified six heterozygous PLN p.Arg14del mutation carriers out of 8,267 subjects (0.07%).

+ Conclusion
The p.Arg14del mutation in the PLN gene is the most frequently identified mutation in Dutch cardiomyopathy patients. The mutation that arose 575-825 years ago is likely to have originated from the eastern part of the province of Friesland and is highly prevalent in the general population in the northern part of the Netherlands.

Spreiding 1 van PLN mutatiedragers

Postcodekaart van Nederland toont de spreiding van PLN p.Arg14del mutatiedragers. Het aantal PLN p.Arg14del mutatiedragers per regio is weergegeven. (Tussen haakjes: het aantal regio’s, 90 in totaal). Iedere regio telt gemiddeld 180.000 inwoners.

Spreiding 2 van PLN mutatiedragers

Postcodekaart van Nederland toont de waarschijnlijke herkomst van het PLN p.Arg14del haplotype. De gegevens zijn gebaseerd op de geboorteplaatsen van de grootouders van de PLN p.Arg14del mutatiedragers. (Tussen haakjes: het aantal regio’s, 90 in totaal). Iedere regio telt gemiddeld 180.000 inwoners.


van der Zwaag PA et al. Neth Heart 2013;21:286–293 doi: 10.1007/s12471-013-0401-3

In 2012 is onze eerste publicatie over de p.Arg14del mutatie in het PLN gen verschenen in het European Journal of Heart Failure. Hieronder kunt u het abstract lezen. Voor het volledige artikel gaat u naar de website van het European Journal of Heart Failure.

Phospholamban R14del mutation in patients diagnosed with dilated cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy: evidence supporting the concept of arrhythmogenic cardiomyopathy

+ Abstract


+ Aims
To investigate whether phospholamban gene (PLN) mutations underlie patients diagnosed with either arrhythmogenic right ventricular cardiomyopathy (ARVC) or idiopathic dilated cardiomyopathy (DCM).

+ Methods and Results
We screened a cohort of 97 ARVC and 257 DCM unrelated index patients for PLN mutations and evaluated their clinical characteristics. PLN mutation R14del was identified in 12 (12 % ) ARVC patients and in 39 (15 % ) DCM patients. Haplotype analysis revealed a common founder, estimated to be between 575 and 825 years old. A low voltage electrocardiogram was present in 46 % of R14del carriers. Compared with R14del– DCM patients, R14del+ DCM patients more often demonstrated appropriate implantable cardioverter defibrillator discharge (47 % vs. 10 % , P < 0.001), cardiac transplantation (18 % vs. 2 % , P < 0.001), and a family history for sudden cardiac death (SCD) at < 50 years (36 % vs. 16 % , P = 0.007). We observed a similar pattern in the ARVC patients although this was not statistically significant. The average age of 26 family members who died of SCD was 37.7 years. Immunohistochemistry in available myocardial samples revealed absent/depressed plakoglobin levels at intercalated disks in five of seven (71 % ) R14del+ ARVC samples, but in only one of nine (11 % ) R14del+ DCM samples (P = 0.03).

+ Conclusions
The PLN R14del founder mutation is present in a substantial number of patients clinically diagnosed with DCM or ARVC. R14del+ patients diagnosed with DCM showed an arrhythmogenic phenotype, and SCD at young age can be the presenting symptom. These findings support the concept of ‘arrhythmogenic cardiomyopathy.


van der Zwaag PA et al. Eur J Heart Fail. 2012;14:1199-1207. doi: 10.1093/eurjhf/hfs119

 

Al deze publicaties kunt u in onze rubriek “Nieuws” in de Nederlandse taal terugvinden en verder lezen.